Cognitive effects of early life exposure to PCBs in rats: Sex-specific behavioral, hormonal and neuromolecular mechanisms involving the brain dopamine system

Endocrine-disrupting chemicals (EDCs) are environmental toxicants that disrupt hormonal and neurodevelopmental processes. Among these chemicals, polychlorinated biphenyls (PCBs) are particularly concerning due to their resistance to biodegradation and tendency to bioaccumulate. PCBs affect neurodevelopmental function and disrupt the brain's dopamine (DA) system, which is crucial for attentional, affective, and reward processing. These disruptions may contribute to the rising prevalence of DA-mediated neuropsychiatric disorders such as ADHD, depression, and substance use disorders. Notably, these behaviors are sexually dimorphic in part due to differences in sex hormones and their receptors, which are targets of estrogenic PCBs. Therefore, this study determined effects of early life PCB exposure on behaviors and neurochemistry related to potential disruption of dopaminergic signaling. Male and female Sprague Dawley rats were exposed to the PCB mixture Aroclor 1221 (A1221) or vehicle perinatally and then underwent a series of behavioral tests in adulthood, including the sucrose preference test to measure anhedonia, conditioned orienting to assess incentive-motivational phenotype, and attentional set-shifting to evaluate cognitive flexibility and response latency. Following these tests, rats were euthanized, and serum estradiol (E2), DA cells in the midbrain ventral tegmental area (VTA) and substantia nigra (SN), and gene expression from those combined midbrain nuclei were measured. Female rats exposed perinatally to A1221 exhibited decreased sucrose preference, and both male and female A1221 rats had reduced response latency in the attentional set-shifting task compared to vehicle counterparts. Conditioned orienting and serum estradiol (E2)were not affected in either sex; however, A1221-exposed rats of both sexes displayed higher TH+ cell numbers in the VTA and increased expression of dopamine receptor 1 (Drd1) in the combined midbrain nuclei. Additionally, E2 uniquely predicted behavioral outcomes and VTA DAergic cell numbers in A1221exposed female rats, whereas DA signaling genes were predictive of behavioral outcomes in males. These data highlight sex-specific effects of A1221 on neuromolecular and behavioral phenotypes.